Over the past decade, there has been increasing interest in the use of cluster boron compounds as pharmacophoric units in drug design. For example, carboranes, which are icosahedral clusters comprised of boron, carbon, and hydrogen, demonstrate high chemical stability and may be incorporated into small molecules as analogs of aromatic hydrocarbons. Because each of the vertices of a cluster boron compound may be derivatized through substitution chemistry, these clusters may serve as rigid scaffolds upon which to build molecules with well-defined, three-dimensional conformations. In addition to hydrophobic interactions, it has been elucidated that carboranes bind strongly with biomolecules through a unique form of hydrogen bonding.
Nicotinamide Phosphoribosyltranferase is the first and rate limiting enzyme in the mammalian NAD+ recycling pathway, converting nicotinamide to nicotinamide mononucleotide (NMN). Owing to the many disparate physiological roles and the cellular compartmentalization of NAD+, this vital enzyme has been given different names (visfatin, pre-B cell colony enhancing factor (PBEF), NAmPRTase and Nampt). It has recently been shown that Nampt activity plays a central role in metabolism, cellular proliferation, cell survival, and inflammatory response, making this enzyme a new target for the treatment of many diseases, including cancer, Alzheimer's, diabetes and arthritis.
Very few compounds have been shown to have activity against Nampt. FK866 is one example, however, there remains a need to provide a new class of molecules able to modulate Nampt. Further, there remains a need for compounds with enhanced biological properties.